We report on a detailed NMR spectroscopic study of the catalyst-substrate interaction of a highly enantioselective oligopeptide catalyst that is used for the kinetic resolution of trans-cycloalkane-1,2-diols via monoacylation. The extraordinary selectivity has been rationalized by molecular dynamics as well as density functional theory (DFT) computations. Herein we describe the conformational analysis of the organocatalyst studied by a combination of nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC)-based methods that resulted in an ensemble of four final conformers. To corroborate the proposed mechanism, we also investigated the catalyst in mixtures with both trans-cyclohexane-1,2-diol enantiomers separately, using advanced NMR methods such as T relaxation time and diffusion-ordered spectroscopy (DOSY) measurements to probe molecular aggregation. We determined intramolecular distance changes within the catalyst after diol addition from quantitative NOE data. Finally, we developed a pure shift EASY ROESY experiment using PSYCHE homodecoupling to directly observe intermolecular NOE contacts between the trans-1,2-diol and the cyclohexyl moiety of the catalyst hidden by spectral overlap in conventional spectra. All experimental NMR data support the results proposed by earlier computations including the proposed key role of dispersion interaction.

Band selective techniques offer the highest sensitivity of all pure shift approaches and thus are the best choice for decoupling well-separated H-frequency regions, such as the amide- or the α-proton region of α-peptides. They are inept to fully decouple the amide- and the α-proton region simultaneously, though. Herein, we present a new homonuclear decoupling technique, which extends the capabilities of band selective decoupling using the perfect echo principle. This modification allows a complete backbone decoupling (amide- and α-protons) in peptides and opens band selective homonuclear decoupling to substances with two mutually coupled protons in the spectral range of interest.

Residual dipolar couplings (RDCs) are amongst the most powerful NMR parameters for organic structure elucidation. In order to maximize their effectiveness in increasingly complex cases such as flexible compounds, a maximum of RDCs between nuclei sampling a large distribution of orientations is needed, including sign information. For this, the easily accessible one‐bond 1H–13C RDCs alone often fall short. Long‐range 1H–1H RDCs are both abundant and typically sample highly complementary orientations, but accessing them in a sign‐sensitive way has been severely obstructed due to the overflow of 1H–1H couplings. Here, we present a generally applicable strategy that allows the measurement of a large number of 1H–1H RDCs, including their signs, which is based on a combination of an improved PSYCHEDELIC method and a new selective constant‐time β‐COSY experiment. The potential of 1H–1H RDCs to better determine molecular alignment and to discriminate between enantiomers and diastereomers is demonstrated.

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Wir stellen eine umfassende NMR‐spektroskopische Untersuchung der Katalysator‐Substrat‐Wechselwirkungen eines hochselektiven Oligopeptid‐Katalysators vor, welcher für die kinetische Racematspaltung von trans‐Cycloalkan‐1,2‐diolen via Monoacylierung verwendet wird. Die außerordentliche Selektivität wurde basierend auf Molekulardynamik‐Simulationen sowie DFT‐Rechnungen erklärt. In dieser Arbeit beschreiben wir die Konformationsanalyse des Organokatalysators durch Kombination des Kern‐Overhauser‐Effekts (NOE) mit residualen dipolaren Kopplungen (RDC), wobei ein Ensemble aus vier Konformeren erhalten wurde. Zur Bestätigung des postulierten Mechanismus untersuchten wir den Katalysator in Mischungen mit dem jeweiligen Enantiomer des trans‐Cyclohexan‐1,2‐diols. Zur Charakterisierung der molekularen Aggregation wurden weiterführende NMR‐Methoden, wie die Messung von T1‐Relaxationszeiten und DOSY‐Experimente, angewendet. Bei der Messung quantitativer NOEs konnte eine Änderung der intramolekularen Abstände innerhalb des Katalysators nach Zugabe des Diols festgestellt werden. Schließlich erlaubte die Entwicklung eines pure‐shift‐EASY‐ROESY‐Experiments auf der Basis von PSYCHE‐Homoentkopplung die direkte Beobachtung intermolekularer NOE‐Kontakte zwischen dem trans‐1,2‐Diol und dem Cyclohexyl‐Rest des Katalysators, welche zuvor aufgrund von Signalüberlagerung in konventionellen NMR‐Spektren nicht beobachtbar waren. Sämtliche experimentellen NMR‐Daten bestätigen die zuvor durch Berechnungen aufgestellten Modelle. Dies beinhaltet auch die vorgeschlagene Schlüsselrolle von Dispersionswechselwirkungen.

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NMR Spectroscopy In their Communication on page 15754 ff., P. R. Schreiner, C. M. Thiele et al. apply newly developed NMR experiments to confirm the mechanism of a highly enantioselective acylation reaction. Dispersion interactions between catalyst and substrate are key to the reaction.